1. Field of the Invention
This invention relates to a process for preparing a steroidcarboxylate. More particularly, it relates to a process for preparing an alkali metal salt of a 3-(17.beta.-hydroxyandrosten-3-one 3-acetal-17.alpha.-yl)propiolic acid (hereinafter referred to as HAP).
2. Description of the Prior Art
The alkali metal salt of HAP prepared by the process of the invention is useful as an intermediate in the preparation of 3-(3-oxo-7.alpha.-acetylthio-17.beta.-hydroxyandrost-4-en-17.alpha.-yl)-pr opiolactone (hereinafter referred to as "spironolactone") which is in turn useful as anti-aldosteronic diuretics and hypotensive agents and which are prepared from the alkali metal salt of HAP according to the following equation: ##STR1##
For the preparation of the spironolactone a process has been known which starts from 3.beta.-hydroxyandrost-5-en-17-one. According to the process, 3.beta.-hydroxyandrost-5-en-17-one is ethynylated and then reacted with carbon dioxide to give a propiolic acid derivative, which is then hydrogenated into an acrylic acid derivative.
The acrylic acid derivative is then converted by acid treatment into 3-(3.beta.,17.beta.-dihydroxyandrost-5-en-17.alpha.-yl)acrylolacetone, which is hydrogenated into a saturated lactone, which is subsequently subjected to the Oppenauer oxidation to give a 3-(17.beta.-hydroxyandrost-4-en-3-on-17.alpha.-yl)propiolactone [see, J. A. Cella, E. A. Brown and R. R. Burtner, J. Org. Chem., 24, 743 (1959)].
The resulting 3-(17.beta.-hydroxyandrost-4-en-3-on-17.alpha.-yl)propiolactone is thereafter dehydrogenated at the 6,7-positions and then reacted with thioacetic acid to give the spironolactone [see, J. A. Cella and R. C. Tweit, J. Org. Chem., 24, 1109 (1959)].
One of the disadvantages of the above-mentioned process is the use of 3.beta.-hydroxyandrost-5-en-17-one as a starting material which involves some problems as described hereinafter. Another disadvantage of the process is that it is complicated due to the great number of steps involved therein.
3.beta.-Hydroxyandrost-5-en-17-one used in the prior art process is prepared, via a complicated process comprising 6 steps, from diosgenin which is extracted from the roots of Dioscorea, one of Bardasco, naturally growing in mountainous regions in Mexico. For this reason in combination with the difficult culture of Bardasco, 3.beta.-hydroxyandrost-5-en-17-one becomes increasingly very expensive.
On the other hand, a process capable of preparing inexpensively androst-4-ene-3,17-dione has been developed in recent years, which process resorts to microbiological oxidation of steroids such as cholesterol derived from fish oil or wool grease recoverable from waste washings of wool.
Thus, it is an object of the invention to provide a simpler process for preparing an alkali metal salt of HAP that is an important intermediate for the spironolactone, starting from the inexpensive androst-4-en-3,17-dione instead of the costly 3.beta.-hydroxyandrost-5-en-17-one.
It has already been known that the HAP alkali metal salts can be prepared from androst-4-ene-3,17-dione. For example, Japanese Patent Laid-Open (Kokai) No. 28157/1978 describes that lithium 3-(17.beta.-hydroxyandrost-4-en-3-one 3-acetal-17.alpha.-yl)propiolate is obtained by reacting 17.beta.-hydroxypregn-4-en-20-yn-3-one 3-acetal with an organolithium compound and reacting the resulting lithium salt of 17.beta.-hydroxypregn-4-en-20-yn-3-on 3-acetal with carbon dioxide. While this process has an advantage in that metallization can be directly performed, the alkyl lithium used in the metallization is difficult to handle and expensive. Accordingly there is a need for improvement in the process.